Autonomic pharmacology Flashcards
What do PNS pre and post galnglonic neurones rleease
ACh
What do SNS pre and post ganglionic synpases release
Pre: ACh
Post”: NAd
What do most autonomic drugs target
target junctional communication so from post ganglionic neurones and the heart or blood vessel
What is the effect of sympatehtic stimulation
- Increases heart rate and contractility (beta 1 receptor )
- vasoconstriction (alpha 1 and 2)
- some vasodilation (beta 2)
- regulations of renin release for volume control (beta 1)
Which receptor increases HR and contractility
Beta 1 adrenorepcetor
Which recpetor can cause vasoconstriction
alpha 1 and 2
which receptor can cause vasodilation
beta 2
Name a drug that is an alpha 1 agonist
midodrine
Name an alpha 2 agonist
clonidine
Name a beta 1 agonist
dobutamine
Name a beta 2 agonist
Salbutamol
Name a alpha 1 antagonust
doxazosin
Name an beta 1 anatgonist
metoprolol
beta blocker
What happens if you activate a beta adrenoreceptor 1
- increased heart rate (positive chronotropic effect)
- Increased contractility rate (positive inotropic effect)
- Increased automaticity
- tendency to induce a spontaneous rhythm
- important when heart is not generating any rhythm during asytole
- important for use of adrenaline in resuscitation
- Fast relaxation and recovery (lusitropic effect)
- important for cardiac filling
How does a beta 1 agonist work
so like the mechanism
Beta 1 mediated pathway → will activate Gs → adenyl cyclase → cAMP, and PKA
beta 1 agonist mechanism
What does PKA target
- Increass ICa,L (Ca2+ channel) for greater Ca2+ entry
- Increased IK for faster repolarization
- Increased Na+/K+ ATPase activity
-Increased If (funny current) for positive chronotropic
- Increased SR Ca2+ uptake (via phospholamban inhibition of SERCA)
- important for lusitropic effect, once ca2+ is released it needs to be removed by SERCA.
- BY increasing rate of reuptake, cardiomyocytes can remove calcium quicker which means faster relaxation
- Increased Ca2+ sensitivity
Clinical use of agonists
What is the clinical use of adrenaline
anaphylaxis
- (you have massive vasodilation, so having alpha 1 agonist opposes alpha one dilation)
-asystole (no electrical rhythm) ventricular fibrillation (after you’ve done DE-fib and other severe arrhythmias (low cardiac output)
What is the mechanism that adrenaline works by
so what recpetor does it bind to, and what does it do
when injected locally → causes vasoconstriction (at alpha 1 adrenoreceptors)
what can adrenaline be mixed with
local anasethtics
What receptor does dobutamine act on
beta 1 adrenoreceptors
is Dobutamine an agonist
Yes
agonists clinical uses
How does dobutamine work
α1 adrenoreceptor coupled to Gq -> Activation of IP3 -> IP3-mediated Ca2+ release from SR -> causes contraction.
alternative pathways PKC, and Rho-kinase
If you are wondering why it’s a beta 1 and alpha agonist, it administered as a racemic mixture, which means it can do a bunch of stuff
What is dobutamine used to treat
- used to treat cardiogenic shock by providing “inotropic support”
- when cardiac output is very low
Clinical uses of agonists
What receptor does phenlyephrine act on
alpha 1
What does Phenylephrine cause
causes vasoconstriction
Why do we use phenylephrine
used to treat nasal congestion
sudafed
What receptor does Midodrine act on
alpha 1
Is Midodrine an agonist or antagonist
agonist
Why do we use Midodrine
used for postural hypotension in autonomic failure
How does Midodrine work for people
like what does it do for their body
- it causes alpha 1 mediated vasoconstriction, which keeps up total peripheral resistance
- therefore more blood is shunted centrally, so more able to cope with postural changes
Vasoconstriction with venoconstriction (increased capacitance)
What medication to we also use to treat postural hypotension with
a mineralocorticoid to increase circulating volume (fludrocortisone)
What is droxidopa
Prodrug for noradrenaline (by analogy with dopa for dopamine)
What is the use of droxidopa
used for short-term in postural hypotension in autonomic failure
Can you name two alpha 2 adrenoreceptor agonists and their uses
Clonidine
- centrally acting antihypertensive acts by decreasing drive
Brimonidine (direct transcutaneous vasoconstriction) for Rosacea
- to oppose this we use alpha 2 agonsit topically, causes contraction of blood vessels after being absoped by skin
Is Doxazosin an agonist or antagonist
anatgonist
Why do we use doxazosin
Used to treat: hypertension, Raynaud’s syndrome (inappropriate or excessive cutaneous vasoconstriction)
What is the mechanism behind Doxazosin
what does it aim to do and how
Causes vasodilation, by opposing resting tone
How?
blocks alpha 1 adrenoceptors, causes vasodilation to oppose sympathetic activity
Are beta blockers agonists or antagonists
antagonists
Name some beta blockers, and what recpetors they target
Propranolol (beta1/beta 2), metoprolol, (beta 1)
atenolol (beta 1)
What are the effects of beta blockers
- Negative chronotropic actions
- slows down heart rate
- Negative inotropic actions
- decrease contractility
- Inhibits automaticity
- Hence, decrease the work done by the heart
- Anti-platelet aggregation
- Used to treat: angina, heart failure, cardiac arrhythmias (antidysrhythmic drugs), hypertension
In agina the main use → through decreasing workload of heart
What drug targets both alpha and beta adrenoceptors
Carvedilol
What do we use carvedliol
heart failure
How does carvedilol work
inhibits a particular cardiac potassium channel
- block alpha-adrenoceptor
- causes drop in blood pressure
- which decreases total peripheral resistance
- which decreases after load
How do beta blockers decrease BP
- Decrease cardiac output, especially during exercise, stress etc
- may lead to “resetting” of baroreceptors (in hypertension).
- beta 1-receptors in the kidney lead to renin release
- renin leads to the production of angiotensins ( vasoconstriction and fluid retention).
- Inhibit the trophic effects of catecholamines in the heart (inhibit cardiac hypertrophy associated with both hypertension and heart failure)
What are the parasympathetic effects on the cardiovascular system
Heart
- Negative chronotropic action through action at the sinoatrial node
- Slow AV node conduction
- Little effect on myocardial contractility
- may be involved in vagal modulation of ventrciualr rhythm
Blood Vessels:
- Limited vasodilation, because of limited innervation (despite widespread endothelial mAChRs)
- Complicated by muscarinic receptor-induced release of NO from endothelial cells
What is teh name of the main muscarnic recpetors on teh heart
mostly M2 recpetprs in the heart
mediated by mediated by Gi (inhibits adenyl cyclase)
so opposite to beta adrenergic responses
What are the two main M2 mediated signalling pathways
1) Direct G-protein-meditated activation of k chnanles
-causes hyperpolarisation of cardiomyocytes
(2) Inhibition of adenylate cyclase (ADC) - opposes PKA-mediated actions on some channels
What is the name of an antagonist that blocks M2 receptors
Atropine
Does atropine only target M2 recpetors on the heart
NO, it can also block all M2 receptors
- decreased secretions (mouth, airways, gut)
- bronchodilation
- constipation
- urinary retention
- pupillary dilation
- confusion/hallucinations
Why do we use atropine clinically
and what are the effects in these scenrioes
Bradycardia following MI with hypotension
-PNS slows down HR so you can increase HR by opposing PNS activation.
Excessive bradycardia with beta-blocker use
-Beta blockers reduce sympathetic drive to tone
-can block PNS actiavtion of heart
Intra-operative bradycardia
-Deep anaesthesia with supress sympathetic drive to heart
-so heart rate gets lower
-so theres atropine on standby
Can you explain how we make noradrenaline, release and recyle it
Synthesis
-tyrosine is converted to DOPA (dihydroxyphenylalanine)
-DOPA is converted to dopamine
-then dopamine is converted into noradrenaline
-noradrenaline is then packaged in vesicles
-then it is exocytosed
Reuptake
-NAd is then reuprake by the noradrenaline transporter
-it is then broken down by MAO
How do we effect the uptake of NAd and what drugs do we use
Uptake is mediated by NAT (noradrenaline transporter), you can block the transporter
So what drugs do this
-cocaine
-tricyclic antidepresseants (imipramine)
there’s also non neuronal uptake
What is the main side effects of drugs that block the NAT receptor
cause pro-arrhythmic effects (so basically excessive arrhytmias)
Why?
-increase in spontaneous contraction can cause a pro-arrhythmic effect
-theres an accumilation od NA in extracelluar space
-you get an amplification of symapthetic drive
this increases cardiomyocytes activity (increases automaticity
What is the other way of affecting NAD that isnt is uptake
You can effect MAO
-MAO breaks down Noradreanline
-if you block MAO
- you can amplify noradrengeric signalling,
What do we use MAO inhibitors for
name some drugs
-have been used as anti deppresants
MAO inhibitors e.g phenelzine, iproniazid)
What is the name of the selective MAO small b inhibtor
selegiline
What is the first line treatment for hypertension in pregnancy
Methyldopa
- mixed mechanism of action
- DOPA (decarboxylase inhibition) so less peripheral NAd)
- so there is less synthesis of noradrenaline
- It converted dopamine beta-hydroxylase to alpha methyl norepinephrine an alpha 2 adrenoreceptor agonist
- alpha 2 agonists act in brain to drop sympathetic drive
What drugs can affect the release NAd
Indirectly acting sympathomimetic amines
Drugs
-tyramine
-ephedrine
-amphetamine
How do sympathomimetic amines work
- can cause noradrenaline to be pushed out of sympathetic nerve terminals
- by displacing nordarenline in places
- they indirectly cause noradrenaline to activate receptors in the heart
- have actions that mimic the sympathetic nervous system →which increases cardiac output
What food do we find tyramine in
cheese
- this can cause an increase in blood pressure
- in conjunction with MAO inhibitors
